This invention relates to novel compositions of matter containing optically pure R-(-)-casodex. These compositions possess potent activity in treating prostate cancer, benign prostatic hypertrophy or hyperplasia, acne and hirsutism and other diseases including those that would benefit from a selective androgen antagonist. Optically pure R-(-)-casodex provides this treatment while substantially reducing adverse effects including, but not limited to, gynecomastia, breast tenderness, hot flushes, nausea, vomiting, fatigue, diarrhea and bone pain, which are associated with the administration of the racemic mixture of casodex. Also disclosed are methods for treating the above described conditions in a human while substantially reducing the adverse effects that are associated with the racemic mixture of casodex by administering the R-(-) isomer of casodex to said human.
The active compound of these compositions and methods is an optical isomer of casodex. The preparation of racemic casodex is described in U.S. Pat. No. 4,636,505. Chemically, the active compound is the (-) isomer of N-[4-cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide, also known as 4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'-(trifluorometh yl)propionanilide, hereinafter referred to as casodex. The absolute stereochemistry of the (-) isomer is believed to be R as shown in formula I: ##STR1##
R-(-)-casodex, which is the subject of the present invention, is not presently commercially available. All of the clinical studies that have been reported have utilized the racemic mixture.
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is (+). For a given chemical structure, these chiral compounds exist as a pair of enantiomers which are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the beta-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer has been believed to be a potent teratogen.
The chromatographic separation of a diastereomeric pair of R-camphanoyl esters of racemic casodex and their hydrolysis and oxidation to (+)-casodex and (-)-casodex on a milligram scale is described by Tucker and Chesterson, J. Med. Chem. 31, 885-887 (1988). The ED.sub.50 of R-(-)-casodex in inhibiting androgen in rats was reported to be 0.5 mg/kg in vivo.
Racemic casodex is presently in clinical trials for use in prostate cancer. [See Kennealey and Furr, Urol. Clin. North Am. 18, 99-110 (1991), Mahler and Denis, J. Steroid Biochem. Molec. Biol. 37, 921-924 (1990); and Newling, Eur. Urol. 18 (Suppl), 18-21 (1990)]. The results of the preliminary clinical studies indicate that racemic casodex may be clinically useful in treating prostate cancer and other androgen-dependent diseases because of its antagonist activity at peripheral androgen receptors.
Androgens have been implicated in the progression of several diseases, including human prostate cancer, where they appear to provide the major hormonal support for cancer cells. It is generally accepted that antiandrogens can play an important role in the endocrine treatment strategy for patients with prostate cancer. Racemic casodex has been found to be a very selective antagonist at peripheral androgen receptors with little if any agonist component and no progestational or glucocorticoid activity.
In human volunteers doses of 10-50 mg p.o. per day resulted in a 50 to 60% reduction in prostatic acid phosphatase levels. Over half the patients receiving racemic casodex at 30 or 50 mg reported gynecomastia and breast tenderness, about 20% reported hot flushes, and less than 10% reported nausea and vomiting, bone pain, confusion, constipation, headache, diarrhea, dyspepsia, fatigue, dizziness or rash. Significant but mild elevations of serum testosterone, estradiol and LH were observed at all doses.
The average half life for racemic casodex, estimated from oral studies, was about 8 days. While clinical trials have so far been limited to prostate cancer, it is believed that as a result of its antiandrogen activity, racemic casodex may also be useful to treat benign prostatic hypertrophy or hyperplasia, acne and hirsutism and other androgen-dependent diseases.
Thus it would be particularly desirable to find a compound with the advantages of the racemic mixture of casodex which would not have the aforementioned disadvantages